Age-related macular degeneration (AMD) is the most important cause of impaired vision in the elderly. The major cause of severe vision loss in AMD is choroidal neovascularization (CNV) or the growth of new vessels under the retina. The pathogenesis of neovascular AMD is multifactorial, but in general, is considered to be driven by angiogenesis, a process in which the cellular components of the new vessel complex are derived from cells from the adjacent pre-existing capillary. However, an alternative mechanism termed "postnatal vasculogenesis", has been shown to contribute to some forms of neovascularization. In vasculogenesis, the cellular components of the new vessel complex are derived, in part, from bone-marrow derived circulating cells. Our group has previously demonstrated that CNV, in animal models, is formed in part from these bone-marrow derived cells. In this proposal, we will confirm and extend these findings to understand the contribution of the various cellular subsets within the circulation which may affect pathogenesis, progression and severity of CNV. Initial work will be done in two rodent models of CNV, the laser-induced and subretinal injection of an adenoviral vector expressing vascular endothelial growth factor. Isolation and depletion experiments will attempt to identify the specific cell types found within the rodent bone marrow which contribute to the CNV. Our group has also demonstrated that these bone-marrow vasculogenic cells can also be identified in the peripheral blood of patients with various degrees of AMD. In subsequent experiments, we will confirm and extend our preliminary human findings and, similar to the preclinical work performed in animals, attempt to identify specific subsets of circulating cells which correlate with disease status. These results will be extended to include confirmatory experiments on patients undergoing surgical excision of CNV and the subsequent histologic analysis of the lesions. In addition, a case-controlled human clinical trial will be performed to further correlate the presence, absence or relative ratios of certain peripheral cells and the ability to predict development, progression or severity of CNV in patients with AMD. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the most important cause of impaired vision in the elderly. The major cause of severe vision loss in AMD is choroidal neovascularization (CNV) or the growth of new vessels under the retina. In this proposal, we seek to understand the contribution of the various cellular subsets within the circulation which may affect pathogenesis, progression and severity of CNV.